This proposal is in response to RFA-DA-04-014, "Medications Development for Cannabis-Related Disorder." The Food and Drug Administration (FDA) recently (January 3, 2003) approved fluoxetine for the treatment of major depression among adolescents and children, based on the results of two acute phase double-blind, placebo-controlled studies (Emslie et al., 1997;2002). Fluoxetine thus became the first antidepressant medication to receive FDA approval for treatment of major depressive disorder (MDD) among adolescents and children. It is unclear to what extent those results apply to adolescents with comorbid MDD and a substance use disorder (SUD) such as cannabis abuse or dependence, since adolescents with SUDs were excluded from participation in that study. However, our own preliminary work suggests that fluoxetine is safe and effective for treating the depression, the cannabis related disorder, and the drinking of comorbid adolescents and young adults (Cornelius et al, 1999;2001;2004). In this study, a first large scale prospective double-blind, placebo-controlled study will be conducted to assess the efficacy of the SSRI medication fluoxetine vs. placebo in the treatment of adolescents with comorbid major depressive disorder and a cannabis related disorder (MDD/CRD). All subjects in both treatment groups will also receive Treatment As Usual (TAU) during the acute phase trial, which will consist of motivation enhancement therapy (MET) and Cognitive Behavioral Therapy (CBT). The goals of this study are: 1) to compare the acute phase (12 week) efficacy of the SSRI medication fluoxetine plus TAU vs. placebo plus TAU for the treatment of the cannabis use and the depressive symptoms of an adolescent and young adult (ages 12-25) sample of subjects with comorbid diagnoses of a CRD (cannabis dependence or cannabis abuse) plus MDD;2) to assess specific predictors of medication response;3) to perform a preliminary evaluation of the longer-term efficacy of fluoxetine in this comorbid population.